Genetic generalized epilepsies

Mullen, Saul A.; Berkovic, Samuel F.

doi:10.1111/epi.14042

Cited by 87 publications

(68 citation statements)

References 40 publications

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“…Despite the predominant genetic etiology of JME, extensive genetic heterogeneity and complex inheritance hinder the molecular genetic dissection of the underlying genetic risk factors. 2,3 Considering that we have applied the same diagnostic criteria for JME and the recruitment scheme, 6,7 the genetic architecture underlying JME should be similar in the original and the present study. Given the high prevalence (>10%) of BRD2 CpG76 hypermethylation in Caucasian JME patients reported in the original study, 6 it is unlikely (P < 10 −5 ) to miss this common epigenetic motif in 116 unrelated European Caucasian JME patients.…”

Section: Discussionmentioning

confidence: 90%

“…Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs), accounting for 5%‐10% of all epilepsies . Genetic factors play a predominant role in the etiology of JME, but the vast majority of the underlying susceptibility genes remain elusive, probably due to an extensive genetic heterogeneity and complex inheritance …”

Section: Introductionmentioning

confidence: 99%

“…1 Genetic factors play a predominant role in the etiology of JME, but the vast majority of the underlying susceptibility genes remain elusive, probably due to an extensive genetic heterogeneity and complex inheritance. [2][3][4] Linkage to the chromosomal region 6p21.3 and association studies of positional candidate genes suggest that the gene encoding the bromodomain-containing protein 2 (gene symbol: BRD2) may increase risk of JME in Caucasians. 4,5 The reported allelic association of JME with the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 and the lack of potentially causative coding mutations suggested that susceptibility of JME could result from a regulatory effect of the promoter SNP on BRD2 expression.…”

Section: Introductionmentioning

confidence: 99%

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No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy

et al. 2019

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Summary Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain‐containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76‐CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy

et al. 2019

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“…This study reaffirms that copy number variation accounts for a small proportion of MAE as for Genetic (idiopathic) generalized epilepsies. 37,38 MAE might be considered as a heterogeneous condition as infantile spasms or LGS with few monogenic cases and with others possible multigenic, epigenetic and/or environmental factors involved in the emergence of MAE.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing findings in 27 patients with myoclonic‐atonic epilepsy: Is there a major genetic factor?

Routier

Verny

Barcia³

et al. 2019

Clinical Genetics

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Myoclonic‐atonic epilepsy (MAE) is thought to have a genetic etiology. Mutations in CHD2, SLC2A1 and SLC6A1 genes have been reported in few patients showing often intellectual disability prior to MAE onset. We aimed to explore putative causal genetic factors in MAE. We performed array‐CGH and whole‐exome sequencing in 27 patients. We considered non‐synonymous variants, splice acceptor, donor site mutations, and coding insertions/deletions. A gene was causal when its mutations have been already linked to epilepsy or other brain diseases or when it has a putative function in neuronal excitability or brain development. We identified candidate disease‐causing variants in 11 patients (41%). Single variants were found in some known epilepsy‐associated genes (namely CHD2, KCNT1, KCNA2 and STXBP1) but not in others (SLC2A1 and SLC6A1). One new candidate gene SUN1 requires further validation. MAE shows underlying genetic heterogeneity with only few cases linked to mutations in genes reported in developmental and epileptic encephalopathies.

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“…Idiopathic generalized epilepsy (IGE) is a well‐described form of epilepsy that is believed to have strong genetic bases . It accounts for approximately 20% of the adult subjects who attend epilepsy outpatient clinics, and is more common in women .…”

Section: Introductionmentioning

confidence: 99%

Doing without valproate in women of childbearing potential with idiopathic generalized epilepsy: Implications on seizure outcome

et al. 2019

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Objective: Valproate (VPA) use in women with idiopathic generalized epilepsy (IGE) who are of reproductive age has been a matter of concern and debate, which eventually led to the recent restrictions by regulatory agencies. The aim of our study was to investigate the relationship between VPA avoidance/switch and seizure outcome in women of childbearing potential. Methods: We retrospectively reviewed data from female patients with IGE, 13-50 years of age, followed since 1980. We evaluated the prescription habits, and the rate of VPA switch for other antiepileptic drugs (AEDs) and its prognostic implications. Seizure remission (SR) was defined as the absence of any seizure type more than 18 months before the last medical observation. The main aim of the study was to assess (a) possible changes in seizure outcome related to VPA switch for other AEDs, especially in patients planning a pregnancy; and (b) possible differences in SR based on the presence/absence of VPA at last observation. Results: One hundred ninety-eight patients were included in the study. Overall SR at last medical observation was 62.7%. SR significantly differed between subjects taking and those not taking VPA (P < .001) at last visit. Multiple regression models showed that taking VPA at last medical observation was strongly associated with SR in both the general population (P < .001) and the juvenile myoclonic epilepsy (JME) group (P < .001). Thirty-six (70.6%) of 51 patients who switched from VPA during follow-up experienced a clinical worsening. Switching back to VPA was more frequently associated with SR at last observation (P < .001). In those patients who substituted VPA in view of a pregnancy, SR and drug burden (monotherapy vs polytherapy) differed significantly before and after the switch. Significance: Our study suggests that VPA avoidance/switch might be associated with unsatisfactory seizure control in women with IGE who are of childbearing potential. Our findings further highlight the complexity of the therapeutic management of female patients of reproductive age. |CERULLI IRELLI Et aL.

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Genetic generalized epilepsies

Cited by 87 publications

References 40 publications

No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy

No evidence for a BRD2 promoter hypermethylation in blood leukocytes of Europeans with juvenile myoclonic epilepsy

Exome sequencing findings in 27 patients with myoclonic‐atonic epilepsy: Is there a major genetic factor?

Doing without valproate in women of childbearing potential with idiopathic generalized epilepsy: Implications on seizure outcome

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